Donanemab interacts in the following cases:
ApoE ε4 carriers have a higher frequency (homozygotes greater than heterozygotes) of ARIA-E and ARIA-H, including serious and symptomatic ARIA, compared to non-carriers. Donanemab is not indicated in patients who are ApoE ε4 homozygotes. Testing for ApoE ε4 carrier status should be performed prior to initiation of treatment to inform the risk of developing ARIA. Prior to testing, prescribers should discuss with patients the risk of ARIA across genotypes.
There are no or limited amount of data from the use of donanemab in pregnant women. A weight-of-evidence approach does not indicate direct or indirect harmful effects with respect to reproductive toxicity.
As a precautionary measure, it is preferable to avoid the use of donanemab during pregnancy.
It is unknown whether donanemab is excreted in human milk. Human immunoglobulin G (IgG) is known to be excreted in breast milk during the first days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to breast-fed infants cannot be excluded during this short period. Afterwards, use of donanemab could be considered during breast-feeding only if clinically needed.
There are no data on the effects of donanemab on human fertility. No animal studies have been performed to test donanemab for potential fertility impairment.
Donanemab has major influence on the ability to drive and use machines if neurological deficits occur, for example visual disturbances, alteration of consciousness and seizures.
In a placebo-controlled pivotal study including patients with mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease, a total of 853 adult subjects received at least one dose of donanemab. Of these, 710 participants concerned the indicated population (ApoE ε4 heterozygotes and non-carriers).
Based on the ApoE ε4 carrier status of the patients treated with donanemab, 29.9% (255/853) were non-carriers, 53.0% (452/853) were heterozygotes and 16.8% (143/853) were homozygotes. With the exception of events of ARIA, the safety profile was similar across genotypes.
The most frequently reported adverse reactions were ARIA-E (20.6%), ARIA-H (27.6%), and headache (14.6%). The most important serious adverse reactions were: Serious ARIA-E (1.3%), serious ARIA-H (0.3%), and serious hypersensitivity, including infusion-related reactions (0.4%). Anaphylactic reaction was uncommonly reported (0.4%).
Adverse reactions from clinical studies with donanemab are listed by MedDRA system organ class. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000).
Adverse reactions:
| System organ class | Very common | Common | Uncommon |
|---|---|---|---|
| Nervous system disorders | ARIA-Ea,b ARIA-Ha,b Microhaemorrhage Superficial siderosis Headache | Intracranial haemorrhagec | |
| Gastrointestinal disorders | Nausea Vomiting | ||
| Injury, poisoning and procedural complications | Infusion-related reactiond Hypersensitivity | Anaphylactic reaction |
a As assessed by MRI.
b Symptoms may include headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visual disturbances, speech disturbances, worsening cognitive function, alteration of consciousness, and seizures.
c Includes subdural haematoma, subarachnoid haemorrhage, cerebral haemorrhage, haemorrhagic stroke and cerebrovascular accident.
d Signs and symptoms of infusion-related reactions and hypersensitivity may include erythema, chills, nausea, vomiting, sweating, headache, chest tightness, dyspnoea, and changes in blood pressure.
In the pivotal placebo-controlled study, where donanemab was administered at the dosing regimen of 700 mg every 4 weeks for the first 3 doses, and then 1 400 mg every 4 weeks, ARIA (ARIA-E or ARIA-H) was observed in 33% (234/710) of ApoE ε4 heterozygotes and non-carrier patients treated with donanemab, compared to 13.5% (98/728) of heterozygotes and non-carrier patients on placebo. Serious ARIA events were reported for 1.4% (10/710) of patients treated with donanemab. Fatal cases of ARIA due to donanemab occurred uncommonly in the pivotal study (0.4%, three patients). Clinical symptoms associated with ARIA-E resolved in approximately 80% of patients. ARIA-E symptoms may include headache, confusion, nausea, vomiting, unsteadiness, dizziness, tremor, visual disturbances, speech disturbances, worsening cognitive function, alteration of consciousness, and seizures.
ARIA-E was observed in 20.6% (146/710) of ApoE ε4 heterozygotes and non-carrier patients treated with donanemab compared with 1.8% (13/728) of patients on placebo. The maximum radiographic severity for ARIA-E was mild in 6.2% (44/710) of patients, moderate in 12.7% (90/710) of patients, and severe in 1.4% (10/710) of patients. Symptomatic ARIA-E was reported for 5.6% (40/710) of patients treated with donanemab in the pivotal study. The median time to resolution of ARIA-E was approximately 8.3 weeks. Of the donanemab-treated patients with ARIA-E, approximately 24.3% (35/144) experienced multiple episodes of ARIA-E.
ARIA-H was observed in 27.6% (196/710) of ApoE ε4 heterozygotes and non-carrier patients treated with donanemab compared with 12.2% (89/728) of patients on placebo. The maximum radiographic severity for ARIA-H was mild in 14.4% (102/710) of patients, moderate in 5.5% (39/710) of patients, and severe in 7.6% (54/710) of patients. Symptomatic ARIA-H was reported for 1.1% (8/710) of patients treated with donanemab compared with 0.3% (2/728) of patients on placebo. Isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) was observed in 12.4% (88/710) of donanemab-treated patients compared to 11.5% (84/728) on placebo. Of the donanemab-treated patients with ARIA-H, approximately 35.9% (70/195) of participants experienced multiple episodes of ARIA-H.
The majority of first ARIA radiographic events in the placebo-controlled studies occurred early in treatment (within 24 weeks of initiation of treatment), although ARIA can occur at any time and patients can have more than one episode.
Standard supportive treatment, including corticosteroids may be considered in case of ARIA-E, however the effectiveness of treatment has not been established.
Intracranial haemorrhage was reported in 1.4% (10/710) of ApoE ε4 heterozygotes and non-carrier patients after treatment with donanemab compared to 0.8% (6/728) of patients on placebo. Of these, intracerebral haemorrhage greater than 1 cm was observed in 0.4% (3/710) of donanemab-treated patients and in 0.3% (2/728) in placebo treated patients. Additionally, in a participant with baseline superficial siderosis treated with donanemab in the pivotal study, fatal ARIA-H was reported with concurrent intracerebral haemorrhage.
In the pivotal study, the overall incidence of ARIA was lower in non-carriers (24.7% donanemab vs. 12.0% placebo) and heterozygotes (37.6% donanemab vs. 14.1% placebo) than in homozygotes (55.9% donanemab vs. 21.9% placebo). Among patients on donanemab, ARIA-E occurred in 15.7% of non-carriers and 23.2% of heterozygotes compared to 41.3% of homozygotes. Symptomatic ARIA-E occurred in 3.9% of non-carriers and 6.6% of heterozygotes compared to 8.4% of homozygotes. ARIA-H occurred in 18.8% of non-carriers and 32.5% of heterozygotes compared to 50.3% of homozygotes. Symptomatic ARIA-H occurred in 0.4% of non-carriers, in 1.5% of heterozygotes and in 1.4% of homozygotes. Serious ARIA occurred in 0.8% of non-carriers and 1.8% of heterozygotes compared to 2.8% of homozygotes.
In the pivotal placebo-controlled study, infusion reactions were observed in 8.3% of patients treated with donanemab compared to 0.4% on placebo. Anaphylactic reaction was uncommonly reported (0.4%). Serious infusion reactions or hypersensitivity occurred in 0.4% of patients treated with donanemab compared to 0.1% on placebo.
All patients reporting infusion-related reactions had ADA. Higher ADA titre was associated with increased incidence of infusion-related reactions/immediate hypersensitivity events.
The majority of infusion reactions and hypersensitivity reactions have occurred within the first 4 doses of donanemab, although they can occur at any time. Treatment discontinuations in donanemab treated patients included IRR (3.5%), hypersensitivity (0.6%), and anaphylactic reaction (0.4%), with no discontinuations due to these events in the placebo group.
Rechallenge led to subsequent IRR/hypersensitivity events in about 46.9% of patients, with severity and type of symptoms usually similar to that of initial events.
Prophylactic medicines prior to subsequent infusions did not prevent IRR recurrence.
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